We have previously hypothesized that the mechanism of the antidepressant response to chronic drug therapy includes effects on the mammalian circadian system. This hypothesis is being examined by testing the effects of antidepressant and neuroleptic drugs on the state of the circadian pacemaker that controls daily rhythms of motor activity, temperature and EEG sleep. Progress during the past year indicates that chronic antidepressant drug treatments may share the physiological property of decreasing the level of hypothalamic temperature. This property has been demonstrated for the monoamineoxidase inhibitor clortyline, the serotonin uptake inhibitor fluoxetine, and the antidepressant drug lithium. Preliminary evidence suggests that the neuroleptic drug haloperidol does not decrease hypothalamic temperature. These findings suggest a novel mechanism mediating the antidepressant response to clinically used medications and may help to identify new non-pharmacological treatments for depression. REM sleep suppression is the only common sleep effect of chronic clorgyline and fluoxetine treatment. Tolerance develops to the REM suppressing effects of both drugs. In contrast, although some tolerance develops to the temperature decreasing effect of clorgyline, potentiation develops to the temperature decreasing effect of chronic fluoxetine treatment. These data indicate that chronic antidepressant drug effects on REM sleep and body temperature may be dissociated and not causally related, particularly during chronic fluoxetine treatment. Experiments planned during the coming year are designed to identify possible mechanisms of temperature decreasing effects of antidepressant drugs. New evidence suggests that the pineal hormone melatonin mediates some of the effects of clorgyline on thermoregulation. Experiments underway will also measure the effects of several drugs on levels of amines and brain punches taken from selected brain nuclei known to participate in thermoregulation as well as expression of the central clock that controls the circadian pattern of body temperature.